1. Germline FOXJ2 overexpression causes male infertility via aberrant autophagy activation by LAMP2A upregulation
- Author
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Fu-Rong Bai, Qi-Qian Wu, Yu-Jie Wu, Yan-Qin Hu, Zhi-Xuan Jiang, Hao Lv, Wen-Zhe Qian, Chang Cai, and Jing-Wen Wu
- Subjects
Male ,Cancer Research ,Immunology ,Forkhead Transcription Factors ,Cell Biology ,Up-Regulation ,Cellular and Molecular Neuroscience ,Meiosis ,Mice ,Spermatocytes ,Lysosomal-Associated Membrane Protein 2 ,Testis ,Autophagy ,Animals ,Humans ,Spermatogenesis ,Infertility, Male - Abstract
Spermatogenesis is a complex biological process that produces haploid spermatozoa and requires precise regulation by many tissue-specific factors. In this study, we explored the role and mechanism of Fork head box J2 (FOXJ2, which is highly expressed in spermatocytes) in the regulation of spermatogenesis using a germline-specific conditional Foxj2 knock-in mouse model (Stra8-Cre; Foxj2tg/tg mouse). Foxj2 overexpression in mouse testes led to spermatogenesis failure, which started at the initiation of meiosis, and resulted in male infertility. Lysosomes and autophagy-related genes were upregulated in Stra8-cre; Foxj2tg/tg mouse testes and the number of autolysosomes in the spermatocytes in Stra8-cre; Foxj2tg/tg mice was increased. Chromatin immunoprecipitation-PCR and Dual-luciferase reporter assays showed that Lamp2 (encoding lysosome‐associated membrane protein‐2) was a target of FOXJ2. Foxj2 overexpression increased the expression levels of Lamp2a and Hsc70 (70-kDa cytoplasmic heat shock protein) in the Stra8-cre; Foxj2tg/tg mouse testes. Our results suggested that Foxj2 overexpression in the germ cells of mouse testes affects chaperone-mediated autophagy by upregulating LAMP2A, leading to spermatogenesis failure at the initiation of meiosis, thus resulting in male infertility. Our findings provide a new insight into the function of FOXJ2 in spermatogenesis and the significance of autophagy regulation in spermatogenesis.
- Published
- 2021